Hypercholesterolemia is known to be one of the prime risk factors for ischemic cardiovascular disease, such as arteriosclerosis. Bile acid sequestrants have been used to treat this condition; they seem to be moderately effective but they must be consumed in large quantities, i.e. several grams at a time and they are not very palatable.
MEVACOR.RTM. (lovastatin), now commercially available, is one of a group of very active antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme, HMG-CoA reductase. In addition to the natural fermentation products, mevastatin and lovastatin, there are a variety of semi synthetic and totally synthetic analogs thereof.
The naturally occurring compounds and their semi-synthetic analogs have the following general structural formulae: ##STR1## wherein:
R.sup.3 is hydrogen, C.sub.1-5 alkyl or C.sub.1-5 alkyl substituted with a member of the group consisting of phenyl, dimethylamino, or acetylamino; and
R* is ##STR2## wherein Q is ##STR3## or R.sup.5 -CH; R.sup.5 is H or OH; M is ##STR4## R.sup.6 is hydrogen or hydroxy;
R.sup.2 is hydrogen or methyl; and a, b, c, and d represent single bonds, one of a, b, c or d represents a double bond, or both a and c or both b and d represent double bonds provided that when a is a double bond, Q is ##STR5## or ##STR6## and when d is a double bond, M is ##STR7## Active metabolites of lovastatin which possess a 2,3,5,6,7,8-hexahydronapthyl moiety and a 3-hydroxy group are disclosed and claimed in co-pending application Ser. No. 856,251, filed Apr. 28, 1986. These metabolites are represented by the following general structural formulae:
Copending application Ser. No. 067,503, filed June 29, 1987 discloses and claims active metabolites of lovastatin which possess a 6-exomethylene moiety. These metabolites are represented by the following structural formulae: ##STR8## wherein:
R is C.sub.1-10 alkyl:
R' is hydrogen, C.sub.1-5 alkyl, or C.sub.1-5 alkyl substituted with a member of the group consisting of phenyl, dimethylamino, or acetylamino.
It would be very useful to be able to prepare such 6-exomethylene derivatives in a synthetic scheme from available starting materials.